Project Summary Advanced age is the main risk factor for most chronic human diseases, including tauopathies and Alz- heimer's disease (AD). However the molecular mechanisms underlying the exponential increases later in life remain largely unknown, impeding the development of interventions that prevent or attenuate disease. It has been proposed that senescent cells, which accumulate with aging in many tissues and organs and at sites of age-related pathologies, promote tissue dysfunction. AD is characterized by the accumulation of A? peptide- containing plaques and aggregates of hyper-phosphorylated or misfolded tau. Cells with features reminiscent of senescence have been observed in post mortem AD patient samples, however when these cells were ac- quired in the disease process and their contribution to pathology is unknown. Senescent cells are not merely residents of aged tissues, they develop a complex phenotype, termed the senescence-associated secretory phenotype (SASP), in which they secrete numerous growth factors, cytokines, and proteases that disrupt the architecture and functionality of neighboring cells in the tissue. The critical barrier to testing the idea that se- nescence is implicated in AD in vivo has been the lack of a mouse model that allows for selective elimination of senescent cells. We made use of a biomarker for senescence, p16Ink4a, to generate a novel transgene, INK- ATTAC, which removes p16Ink4a-positive senescent cells upon administration of a synthetic drug. We have fo- cused our studies firstly on understanding whether pathologic tau accumulation drives senescence in a tauopa- thy mouse model. In preliminary studies using a mouse model expressing a mutated form of human tau, we find that elimination of senescent cells prior to disease onset reduces neurofibrillary tangle deposition, neuro- degeneration and memory loss. With these results in mind, we will test our central hypothesis that senescent cells are causally implicated in tau pathology and that removal of senescent cells will have a profound disease- attenuating impact. We propose three specific aims. In the first aim we will determine the identity of the cells that senesce in this model as well as the kinetics of senescent cell accumulation. In the second aim, we will determine the nature and consequences of the secretory phenotype of senescent cells in the brain of our tau mutant model. In the third aim we will establish the therapeutic potential of senescent cell removal in tauopa- thy, where treatment to remove senescent cells is started after disease is established. The overall impact of this project is that it will critically test the untested hypothesis that senescent cells promote neurodegeneration, address key fundamental questions about disease-related senescent cells, identify key components of the SASP that promote tauopathy, and test the entirely novel concept of targeting senescent cells or key elements of the SASP as a therapeutic strategy for tau-mediated disease. This knowledge will pave the way towards transformative clinical interventions for treating or preventing not only tau-dependent disease, but also a broad spectrum of human age-related diseases that limit healthspan, in addition to conceptually advancing the fields of senescent cell biology.